Agomelatine has a chemical structure as shown in Formula (I), with the chemical name N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide and trade name Valdoxan. It has dual pharmacological effects, which is not only the agonist of melatonergic system receptors, but also the antagonist of 5HT2C receptor. Said properties confer activity in the central nervous system, especially in the treatment of major depression, seasonal affective disorders, dyssomnia, cardiovascular diseases, digestive system diseases, insomnia and fatigue caused by jet lag, appetite disorders and obesity. It is the first melatonin type antidepressive agent, which can effectively treat depressive disorders, improve the sleep parameters and maintain sexual function. It was approved by EU on Feb. 24, 2009, with the trade name Valdoxan®/Thymanax®.

Taking into account the compound's pharmaceutical value, it is important to obtain the compound in an effective industrial synthetic method, which can be easily converted into large-scale production in the industry and obtain agomelatine in good yield and high purity.
Many synthetic methods for agomelatine have been reported, which can be roughly divided into four types, in which all of the starting materials are the compound of formula (II). European patent specification EP0447285 reported a method for preparation of agomelatine (I): reacting 7-methoxy-tetralone (II) with ethyl bromoacetate by Reformatsky reaction, and then dehydro-aromatization with sulfur to obtain (7-methoxy-1-naphthyl)acetic acid ethyl ester (IV), followed by hydrolysis, acyl chlorination, ammonification, dehydration and reduction to yield the compound (VIII), which is finally acetylated to obtain agomelatine (I), as shown below:

However, there are some defects in the above method, which comprise:                (1) it takes eight steps to synthesize 2-(7-methoxy-1-naphthyl)ethylamine, thereby rendering the average yield being less than 30%;        (2) when the above method is converted into industrial scale, it is difficult to carry out the reaction, mainly due to the poor reproducibility of the first step; the first step comprises reacting 7-methoxy-tetralone (II) with ethyl bromoacetate by Reformatsky reaction to produce ethyl (7-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)acetate, which requires benzene as the solvent; considering the environmental factors, said step does not meet the requirements of large-scale production; and        (3) the next step for aromatization of ethyl (7-methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)acetate is usually incomplete, and after saponification often results in a mixture, from which it is difficult to separate pure product (IV).        
Chinese patent specification CN1680284 reported another method for agomelatine synthesis: reaction of 7-methoxy-tetralone (II) with cyano-acetic acid produces intermediate compound (IX), the intermediate (IX) is dehydrogenated in the presence of hydrogenation catalyst Pd-C, with allyl methacrylate as the dehydrogenating agent, followed by reduction to generate compound (VIII), and finally the compound (VIII) is converted to agomelatine (I) by acetylation. The total yield is about 72%, as shown below:

But there are some defects in the above method:                (1) some carcinogenic agents are used in the reaction route, for example, benzylamine/heptanoic acid catalyst system with great toxicity is used in the conversion of formula (II) to formula (IX);        (2) propyl methacrylate is used as the dehydrogenating agent during the conversion of formula (IX) to (VII), which results in a lot of environmental pollution, moreover, this step of reaction actually was found to be low yield and difficult to reproduce; and        (3) during the hydrogenation process of conversion of formula (VII) to (VIII), a by-product having formula (XII) generated; since the nature of the by-product is similar to the desired product and this step is the penultimate step, it is difficult to purify the desired product and the yield loss after recrystallization is large.        

Considering the medicinal value and good market prospects of agomelatine, it is important to synthesize the compound of formula (I) in an effective manner for industrialization.